Imidazolinyl phenyl carbonyl compounds, acid addition salts and related compounds

ABSTRACT

This invention is concerned with tetrahydropyrimidinyl phenyl carbonyl acid addition salts, imidazolinyl phenyl carbonyl acid addition salts, dihydroimidazoisoindolols, tetrahydropyrimidoisoindolols, and tetrahydropyrimidoisoindolol acid addition salts which are all pharmacologically efficacious as anti-depressants. The tetrahydropyrimidinyl phenyl carbonyl acid addition salts, the tetrahydropyrimidoisoindolols and the tetrahydropyrimidoisoindolol acid addition salts are also efficacious as diuretics while the imidazolinyl phenyl carbonyl acid addition salts and the dihydroimidazoisoindolols are efficacious as anorexiants. This invention is also concerned with several processes for the preparation of these compounds.

United States Patent [191 Sulkowski 1 Feb. 18,1975

[ IMIDAZOLINYLPHENYL CARBONYL COMPOUNDS, ACID ADDITION SALTS AND RELATED COMPOUNDS [75] Inventor: TheodoreS. Sulkowski,Wayne, Pa.

[73] Assignee: American Home Products Corporation, New York, N.Y.

[22] Filed: Sept. 6, 1973 [21] App]. No.: 394,706

Related US. Application Data [60] Division of Ser. No. 757,792, Sept. 5, 1968, Pat. No. 3,763,178, which is a continuation-impart of Ser. Nos. 622,918, March 14, 1967, abandoned, and Ser. No. 622,931, March 14, 1967, abandoned, and Ser. No. 576,833, Sept. 2, 1966, abandoned, and Ser. No. 487,587, Sept. 15, 1965, abandoned.

[52] US. Cl 260/296 T [51] Int. Cl. C07d 49/34, C07d 57/02 [58] Field of Search 260/3096, 296 T [56] References Cited UNITED STATES PATENTS 3,803,155 4/1974 Sulkowski et al. 260/2948 R Primary ExaminerLewis Gotts Assistant Examiner-Ethel G. Love Attorney, Agent, or Firm-Stephen Venetianer; Vito Victor Bellino [57] ABSTRACT This invention is concerned with tetrahydropyrimidinyl phenyl carbonyl acid addition salts, imidazolinyl.

phenyl carbonyl acid addition salts, dihydroimidazoisoindolols, tetrahydropyrimidoisoindolols,,

2 Claims, No Drawings IMIDAZOLINYL PHENYL CARBONYL COMPOUNDS, ACID ADDITION SALTS AND RELATED COMPOUNDS This is a division, of application Ser. No. 757,792, filed Sept. 5, 1968, now US. Pat. No. 3,763,178, which in turn is a continuation-in-part of U.S. Pat. application, Ser. No. 622,918, entitled Tetrahydropyrimidinyl Phenyl Carbonyl and lmidazolinyl Phenyl Carbonyl Compounds, filed Mar. 14, 1967; Ser. No. 622,931, entitled Process For the Preparation of lmidazolinyl Phenyl Carbonyl Compounds, filed Mar. 14, 1967;

Ser. No. 576,833, entitled 2-(3-Aminopropyl) lsoindoles and Related Compounds," filed Sept. 2, 1966; and Ser. No. 487,587, entitled l,2,3,4,6,l0b-Hexahydropyrimido[2,l-a]lsoindol-6-Ones and Related Compounds, filed Sept. 15, 1965 and now abandoned.

This invention relates to bicyclic and tricyclic nitrogen containing compounds as well as to novel methods for their preparation. In particular, the present invention is concerned with tetrahydropyrimidinyl phenyl carbonyl acid addition salts, tetrahydropyrimidoisoindolols and tetrahydropyrimidoisoindolol acid addition salts which in standard and accepted pharmacological tests have demonstrated both antidepressant and diuretic activities. Further, it is concerned with imidazolinyl phenyl carbonyl acid addition salts and dihydroimidazoisoindolols which in standard and accepted pharmacological tests have demonstrated both antidepressant and anorexiant activities.

The new and novel compounds which are included within the scope of this invention are represented by the following formulae:

wherein R, and R are selected from the group consisting of hydrogen, lower alkyl, phen(lower)alkyl, phenyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl. di(lower)alkylphenyl, trit'luoromethylphenyl. mono(lower)alkoxyphenyl, di(lower)alkoxypheny|, thienyl, pyridyl, furyl and tetrahydro-2-naphthyl, with the provision that R is hydrogen, lower alkyl and phen(lower)alkyl when n is 2; R is selected from the group consisting of hydrogen, halogen, amino, lower alkylamino, lower alkyl and lower alkoxy; R is hydrogen when R and R are dissimilar and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R is selected from the group consisting of phenyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl, mono(l0wer)alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, furyl and tetrahydro-Z-naphthyl; n is an integer from 1 to 2; and HX is a pharmacologically acceptable acid addition salt. As employed herein the terms lower alkyl," lower alkoxy" and the like are meant to include both branched and straight chain moieties containing from one to about six carbon atoms.

The new and novel compounds of this invention which are represented by structural formula (1) wherein n is l are called lmidazolinyl Phenyl Carbonyl Acid Addition Salts. Typical examples thereof are: 2(Z-imidazolin-Z-yl)benzophenone benzophenone hydrochloride and 4'-chloro-2-(Z-imidazolin-Z- yl)benzophenone hydrochloride. Alternatively, those compounds of structural formula (1) wherein n is 2 are named: Tetrahydropyrimidinyl Phenyl Carbonyl Acid Addition Salts," such as, 2-(3,4,5,6-tetrahydro-2- pyrimidinyl)-4-methylbutyrophenone hydrochloride and 2-phenyl-2-(3,4,5,6-tetrahydro-2- pyrimidinyl)acetophenone hydrochloride.

The new and novel compounds of this invention which are depicted by structural formula (11) wherein n is l are designated Dihydroimidazoisoindolols," for example, 2,3-dihydro-5-phenyl- 5 H-imidazo[ 2, l

N and called Tetrahydropyrimidoisoindolols." such as. 6-(4- chlorophenyl )-2,3,4,6-tetrahydropyrim idol 2, l a]isoindol-6-ol and 2,3,4,6-tetrahydro-6- phenylpy rimido[ 2, l -a]isoindol-6-ol.

The new and novel compounds of this invention which are representedby structural formula (Ill) are named Tetrahydropyrimidoisoindolol Acid Addition Salts." Typical examples thereof are: 6-(4- chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,la]isoindol-6-ol hydrochloride and 2,3,4,6-tetrahydro- 6-phenylpyrimido[2,l-a]isoind0l-6-ol hydrochloride.

In accord with the new and novel first process of this invention, the tetrahydropyrimidoisoindolols of this invention may be produced by the oxidation of 2-(3- aminopropyl)isoindoles, as exemplified by the following reaction scheme:

wherein R R and R are defined as above. Various oxidation processes will readily suggest themselves to those skilled in the art. For example, the particular 2-(3-aminopropyl)isoindole (A) may be dissolved in a reaction-inert solvent, e.g. an alkanol, and purged with oxygen or air until the oxidation is complete. Alternalized from an appropriate solvent, such as dimethylformamide and dimethylacetamide.

In accord with the new and novel second process of the present invention, the dihydroimidazoisoindolols of this invention may be synthesized by the following schematic sequence of reactions:

Rn E; (I) i, (2)

N l 9 l3 .1 2 so R SO2R6 3 c=o 2 u 3 l Ra u N""t J h R2\/ I N wherein R R and R are defined as above, R is aryl and alkyl, for example: lower alkyl, phenyl,

monohalophenyl, dihalophenyl, mono(lower)alkylphenyl, di(lower)alkylphenyl and alkoxyphenyl, and X is In accord with the new and novel third process of the present invention, some of the dihydroimidazoisoindolols of this invention may be prepared by the procedure which is exemplified by the following reaction the anion portion ofa mineral acid. The rearrangement 5 scheme:

ofatetrahydroimidazoisoindolone of formula (1) is cf wherein R is selected from the group consisting of fected by contacting the particular compound (1) with an mineral acid. This reaction may be accelerated by heating and stirring the reaction mixture until the precipitation of the 2-(aminoethyl)-3- hydroxyphthalimidine mineral acid addition salt, as designated in formula (2), is complete. The phthalimidine (2) is separated by filtration or decantation and either recrystallized from a suitable solvent, such as water, a lower alkanol and dioxan, or admixed directly with a substantially equimolar quantity of an aryl or alkyl sulfonyl halide in pyridine. The reaction mixture is then heated to a temperature from about 80C. to about l l5C. for a period from about 2 hours to about 10 hours. Preferably, this reaction is conducted at the reflux temperature of the reaction mixture for a period of about two hours. After the above reaction is complete, the product of sulfonyltetrahydroimidazoisoindolone (3) is recovered by customary isolation procedures.

The above prepared sulfonyltetrahydroimidazoisoindolone (3) may be hydrolyzed and rearranged by admixture with from about 80 to about 100 percent sulfuric acid. The product of this hydrolysis, the sulfate salt of an imidazolinyl phenyl carbonyl compound, as shown in formula (4) which may be recovered as such by conventional means. Alternatively, the reaction mixture is neutralized by the addition ofa base and the resulting precipitate recrystallized from an appropriate organic solvent such as lower alkanol, dioxan, dimethylformamide and dimethylacetamide to afford an appropriate dihydroimidazoisoindolol (5).

As a new and novel alternative to the second process of the present invention, it has been found that the dihydroimidazoisoindolols of this invention may also be prepared by directly reacting a tetrahydroimidazoisoindolone (l with an aryl or alkyl sulfonyl halide under the almvc-described reaction conditions to afford an appropriate sulfonyltetrahydroimidazoisoindolone (3 Thereafter, this compound (3) is further reacted as hereinbefore described to yield an imidazolinyl phenyl carbonyl sulfate salt (4) which may then be neutralized to afford a dihydroimidazoisoindolol (5).

As a further alternative to the second process of the present invention, it should be noted that the 2- (aminoethyl)-3-hydroxyphthalimidine (2) intermediates can also be prepared by the condensation of an acid chloride of an o-carbonyl benzoic acid with ethylene diamine as described by Sulkowski et al in J. Org. Chem. 32, 2180 (1967).

lower alkyl, phenyl, lower alkylphenyl, lower alkoxyphenyl, di(lower)alkylphenyl, di(lower)alkoxyphenyl, aminophenyl, trifluoromethylphenyl, monohalophenyl, dihalophenyl, furyl, thienyl and naphthyl; R is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R is hydrogen when R and R are dissimilar and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy.

The oxidation reaction is effected by contacting an appropriate hexahydrobenzodiazocine (a) with an oxidizing agent in a reaction-inert solvent at a temperature from about 20C. to about C. for a oxidizing of about reaction-inert solvents regard, dichromate reaction-inert hexahydrobenzodiazocine to about 4 hours. Preferably, this reaction is conducted by contacting an aqueous solution of a hexahydrobenzodiazocine salt with a potassium permanganate solution at room temperature for about 1 hour. Many other ocidizing agents and reaction linert which may be employed in this reaction will readily suggest themselves to those skilled in the art. In this reagard, excellent results can be obtained when potassium dichormate and potassium chlorate are employed as the oxidizing agents. By reactionlinert solvent as employed herein is meant a solvent which will dissolve the hexahydrobenzoidazocine and not interfere with the oxidation reaction, such as, water while acetone and methyl ethyl ketone may be employed as solvents when potassium permanganate is employed as the oxidizing agent.

When the oxidation reaction is complete, the corresponding dihydroimidazoisoindolol (b) may be separated and recovered by routine means, for example, precipitating the product by the addition ofa base and then separating it by decantation or filtration. The time and temperature ranges employed in the aforesaid reactions are not critical but simply represent the most convenient range consistent with carrying out these reactions in a minimum of time without undue difficulty. Thus reaction temperatures appreciably below these can be used, but their use considerably extends the reaction time. Similarly, reaction temperatures higher than those mentioned can be employed with a concomitant decrease in reaction time. The 2-(3 aminopropyl)isoindoles (A) employed as starting materials in the first above described process for the preparation of the tetrahydropyimidoisoindolol compounds (B) of this invention are known compounds which are described in co-pending US. Pat. application, Ser. No.

622,9 1 7, entitled lsoindoles, Isoindolines and Related Compounds," filed on Mar. 14, 1967, by Theodore S. Sulkowski which is a continuation-in-part of U.S. Pat. applications, Ser. No. 576,833, entitled 2-(3- Aminopropyl)lsoindoles and Related Compounds, filed Sept. 2, 1966 and Ser. No. 487,587, entitled 1,2,- 3,4,6,lb-Hexahydropyrimido[2,l-a]lsoindol- 6-Ones, filed Sept. 15, 1965 and now abandoned. The tetrahydroimidazoisoindolones (l) and the hexahydrobenzodiazocines (a) which are respectively employed as starting materials in the second and third above described process for the preparation of the dihydroimidazoisoindolols (5) of this invention are known compounds which are described in co-pending U.S. Pat. application, Ser. No. 609,779, entitled Benzodiazocines," filed on Jan. 17, 1967, by Theodore S. Sulkowski, which is a continuation-in-part of U.S. Pat. applications, SerfNo. 554,672, entitled Benzodiazocines," filed on June 2, 1966; Ser. No. 444,050, entitled Substituted 3,4-Dihydro-6-Aryl-2,5- Benzodiazocin-l(2H)-Ones and Related Compounds," filed on Mar. 30, 1965 and now abandoned; and Ser. No. 272,216, entitled Substituted 3,4-Dihydro-6- Aryl-2,5-Benzodiazocin-l(2H)-Ones and Related Compounds, filed on Apr. ll, l963 and now abandoned. The aryl or alkyl sulfonyl chlorides used in this latter process are well known chemicals which are commercially available or may easily be prepared by well known chemical procedures.

The tetrahydropyrimidoisoindolols (B) ofthe present invention were at first thought to be Hexahydropyrimidoisoindolones and were so described in the first prior filed parent application (U.S. Ser. No. 487.587). Subsequently, these compounds were reexamined and then thought to be Tetrahydropyrimidinyl Phenyl Carbonyl Compounds" and were so defined in the following two subsequently filed parent applications (U.S. Ser. Nos. 576,833 and 622,918). It has now been concluded, based on the nature of the starting materials; the mode of synthesis; the elemental analysis; and the ultra violet and infra red spectrographic analyses, that all the solid bases prepared by the first process of this invention are "Tetrahydropyrimidoisoindolols (B). Further, since these nitrogen containing tetrahydropyrimidoisoindolols are basic in nature they will react with pharmacologically acceptable acids to form acid addition salts. Such acids are well known in the art, for exammple, hydrochloric, hydrobrornic, hydroiodic, sulfuric, nitric, phosphoric, acid, lactic, citric, tartaric, maleic, gluconic, benzenesulfonic, toluenesulfonic, methylsulfonic, ethylsulfonic acid and the like. These salts may be prepared by procedures commonly employed in the art, for example, reacting the compound with an equivalent of the selected acid in aque ous solution and concentration of the solution. Other known procedures may also be employed, e.g., the procedure of Example Vlll.

The ultra violet spectrographic analyses of the tetrahydropyrimidosindolols (B) of this invention and their acid additon salts which are substituted in the 6- position with an aromatic group, e.g., phenyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl, mono(lower)alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, fury] and tetrahydro-Z-naphthyl, demonstrate an absence of absorption in the 250 mu region indicating that both the bases and salts possess these tetrahydropyrimidoisoindol structures in solution. Alternatively, ultra violet analyses of neutral and acidic solutions of these tetrahydropyrimidoisoindolols (B) and their acid addition salts which are unsubstituted, e.g. hydrogen or substituted in the 6-position with an aliphatic or aralkyl group, e.g. lower alkyl and phen(- lower)alkyl demonstrate absorption in the 235240 my. region indicating that their structures in solution are predominately the tetrahydropyrimidinyl phenyl carbonyl compounds of the structure:

wherein R and R are defined as above and R is hydrogen, lower alkyl and phen(lower)alkyl. Further, the infra red spectrographic analyses of these latter compounds determined by the procedure of Hofmann et al, Analyt. Chem., Vol. 39, pg. 406 (1967) also indicates that the solid acic addition salts thereof also exist in the above shown tetrahydropyrimidinyl phenyl carbonyl forms.

The dihydroimldazoisoindolols (5) of the present invention were first thought to be Tetrahydroimidazoindolones and were so described in the first prior filed parent application. Subsequently, these compounds were re-examined and then thought to be lmidazolinyl Phenyl Carbonyl Compounds and were so defined in the following three subsequently filed parent applications (U.S. Ser. Nos. 576,833, 622,931 and 622,918). It has now been concluded, based on the nature of the starting materials; mode of synthesis; the elemental analysis; and ultra violet and infra red analyses, that all the solid bases prepared by the second and third process of this invention are Dihydroimidazoisoindolols" (5 Further, since these nitrogen containing dihydroimidazoisoindolols are basic in nature they also will react with pharmacologically acceptable acids as described above to form acid addition salts.

The ultra violet spectrographic analyses of the dihydroimidazoisoindolols (5) of this invention in neutral solution demonstrate an absence of absorption in the 250 my. region indicating that these bases also possess these dihydroimidazoisoindolol structures when they are dissolved in a non-acidic solution. Alternatively, the ultra violet analyses of acid solution of these bases and the neutral solutions of their acid addition salts demonstrate absorption in 250 ma region indicating that they are imidazolinyl phenyl carbonyl compounds in solution of the structure:

where R R and R, are defined as above. The infra red spectrographic analyses of these compounds also indicates that the solid bases are dihydroimidazoisoindolols while their corresponding solid acid addition salts exist in the above shown imidazolinyl phenyl carbonyl forms.

The tetrahydropyrimidinyl phenyl carbonyl acid addition salts (formula I where n is 2); the tetrahydropyrimidoisoindolols (formula II where n is 2); and the tetrahydropyrimidoisoindolol acid additioin salts (formula III) of the present invention have been found to possess valuable pharmacological activity. More particularly, these compounds have exhibited utility, in standard pharmacological tests, as anti-depressant and diuretic agents.

In the pharmacological evaluation of the antidepressant property of these compounds (I, n=2; II, n=2; and III), the in vivo anti-depressant activity is evaluated by the procedure described by Rubin et al, in J.P.E.T. 120, 125 1957). When tested by this procedure, these compounds demonstrate useful antidepressant activity, e.g. having mood elevating properties as psychic energizers, when they are administered orally to mice in a dosage range from about I to about 100 mg./kilo of animal body weight. Further, the in vivo diuretic activity of these compounds (I, n=2; II, n=2; and III) is evaluated by the procedure described by Lipschitz et al, in J. Pharmacol. 79, 97 (1943). When tested by this procedure these compounds demonstrate useful diuretic activity when they are administered orally to rats in a dosage range from about 0.25 to about 25 mg./kilo of animal body weight.

The imidazolinyl phenyl carbonyl acid addition salts (formula I where n is I) and the dihydroimidazoisoindolols (formula II where n is l of the present invention have also been found to possess valuable pharmacological activity. In particular, these compounds have exhibited utility, in standard pharmacological tests, in anti-depresant and anorexiant agents.

In the pharmacological evaluation of the antidepressant property of these compounds (I, n=1 and II, n=l the in vivo anti-depressant activbity is also evaluated by the procedure described by Rubin et al, in J.P.E.T. I20, 125 (1957). When tested by this procedure, these compounds demonstrate useful antidepressant activity, e.g. having mood elevating properties as psychic energizers, when they are administered orally to mice in a dosage range from about I to about mg./kilo of animal body weight. Further, the in vivo anorexiant activity of these compounds (I, n==l and II, n=1), e.g. appetite suppressant effects is evaluated by the following procedure:

Male Charles River rats between 120 and 140 grams are trained to drink sweetened condensed milk from a graduated drinking tube, After a short learning period the animals are placed on a routine of water ad lib for 24 hours, standard laboratory chow for 22 hours and sweetened condensed milk for 2 hours. The volume of milk consumed is measured at /2 hour as well as 2 hours and the animals are weighed daily. This schedule is maintained 5 days a week over a period of several months. Trials are run on the same day each week and changes in milk consumed and 24 hour weight changes are compared to the average of the 2 days before the test compound is administered. Animals are tested as groups of six and one group is given saline each week to serve as controls. The test compounds are usually administered intraperitoneally in saline and/or orally in water.

The imidazolinyl phenyl carbonyl acid addition salts and the dehydroimidazoisoindolols of this invention in the above test procedure when administered orally to rats at a dose of IO mg./kg. induce a decrease in food consumption of about forty percent in the first half hour and about 20 percent in 2 hours with a concurrent total average weight loss of about one-half a gram/animal in 24 hours. When administered intraperitoneally at a dose of 10 mg./kg., these compounds (I, n=1 and II, n=l) induce a decrease in food consumption of about 8 percent in the first half hour and about percent in 2 hours with a concurrent total 24 hour average weight loss of about seven and a half grams/animal.

When the tetrahydropyrimidinyl phenyl carbonyl acid addition salts; the tetrahydropyrimidoisoindolols and the tetrahydropyrimidoisoindolol acid addition saltsof this invention are employed as anti-depressant and diuretic agents and when the imidazolinyl phenyl carbonyl acid addition salts and the dihydroimidazoisoindolol of this invention are employed as anti-depressant and anorexiant agents. they may be administered to mammals, e.g. mice, rats, rabbits, dogs, cats, monkeys, etc. alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical na ture of the compound, chosen route of administration and standard biological practice. For example, they may be administered orally in the solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or tey may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, through saline or glucose to make the solution isotonic.

The dosage of the compounds of this invention will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter,

the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

The following examples are given by way of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the scope of spirit thereof.

EXAMPLE I (pHl) max.

Analysis: Ultra Violet Absorption (95% ETOH) max. 224 my. (e=23,000); infl. 243 mu (e=12,000), max.267 mu (e=3,800); Ultra Violet Absorption 223 mu (=2l,l00), infl. 243 my. (e=l4,200), max. 267 mp. (e==3,800); Infra Red Absorption (KBr) 1652 cm, 2,400-3000cm.

Calcd for C H CIN O: C, 68.33; H, 5.06; N, 9.33;

Found: C, 68.12; H, 5.39; N, 9.22; Cl, 11.85.

The above prepared tetrahydropyrimidoisoindolol is dissolved in ethanol and admixed with an aqueous solution containing an equivalent amount of hydrochloric acid. The mixture is stirred for ten minutes and the solvent removed by evaporation. In this manner, is obtained 6-(4-chlorophenyl)-2,3,4,6- tetrahydropyrimido[2,l-a]isoindol-6-ol hydrochloride, m.p. 232-4C., as a white crystalline solid, which is soluble in hot water.

Analysis: Ultra Violet Absorption (95% ETOH) max. 224 mp. (B=23,000), infl. 243 mu (e=14,000), infl. 268 mp. (e=3,800); Infra Red Absorption (KBr) 1675 cm", 2,600-3,300 cm.

Calcd for C H, ClN O-HCl: C, 60.91; H, 4.81; N,

8.36; Cl, 21.16. Found: C, 60.91; H, 5.06; N, 8.31; Cl, 21.1.

EXAMPLE 11 The procedure of Example 1 is repeated reacting an appropriate 2-(3-aminopropyl)isoindole with an oxidizing agent, e.g. potassium dichromate. potassium chlorate and hydrogen peroxide to afford the hereinafter listed products:

2-( 3-AM1NOPROPYL)1SOINDOLES PRODUCTS 8-bromo-2,3,4.6-tctrahydro- 6-(4tolyl )pyrimidol 2, l -a] isoindol-fi-ol 2.3,4,6-tetrahydro-9- n1ethyl-6-propylpyrimido [2. l-alisoindol--ol 2.3,4,6-tetrahydro- 10- iodopyrimidol2,1-alisoindol -6ol 2-( 3-aminop ropyl )-6- bromol 4-tolyl isoindole 2( 3-aminopropyl )-5- methyl-l -propylisoindole 2-(3-aminopropy1)-4- iodoiso-indole 8.9-dibromo-6-( 4-bromophenyl)-2,3,4.6-tetrahydrogyrimidofl, l -a]isoindo1- 2-(3-aminopropyl )-1- (4-bromo-pheny1)-5,6 dibromoisoindole 2,3,4,6 tetrahydro-6-(2.4- dimethoxyphenyl)pyrimido [2, l -a]isoindol-6-ol 2-( 3-aminopropylJ-1- (2,4-dimethoxyphenyl)- isoindole EXAMPLE lll recrystallization from dimethylformamide there is obtained 2,3,4,6-tetrahydro-6-phenylpyrimido[2,lalisoindol-6-ol, mp 25 5257C. dec., as white prisms which is insoluble in water and slightly soluble in hot dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 233 mu (e=14,000), max. 268 mp. ($4,000), infl. 271 mp. (e=3,000); Ultra Violet Absorption (pHl) max. 239 my. (e=l4,900), infl. 271 mp. (e=3,000); Infra Red 5 Absorption (KBr) 1,650 cm", 2,300-3,000 cm.

Calcd for C H N O: C, 77.25; H, 6.10; N, 10.60.

Found: C, 77.36; H, 6.05; N, 10.51.

The above reaction is repeated in anhydrous diisopropyl ether at 60C. for 2 hours with similar results. 4 In a similar manner, starting with l0b-(3',4'- dichlorophenyl)-l,2,3,4,6.l0b-hexahydropyrimido[2,l-a]isoindol-6-one there is obtained 6- (3,4-dichlorophenyl)-2,3,4,6,-tetrahydropyrimido[2,1- a]isoindol-'6-ol, m.p. 267269C., as a white crystalline solid which is insoluble in water and slightly soluble in hot dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) infl. 230 mu (e=22,600), max. 268 mu (e=4,500); infl. 282 mu (e=2,000); Ultra Violet Absorption (pHl) max. 228 mp. (e=22,000), max. 268 mp. (F4,700); infl. 282 mu (e=1,600); Infra Red Absorption (KBr) 1650 cm, 2300-3000 cm.

Calcd for C H Cl N O: C, 61.27; H, 4.24; N, 8.41;

Cl, 21.29. Found: C, 61.41; H, 4.28; N, 8.46; Cl. 21.2.

EXAMPLE lV 2-(3-Aminopropyl)-l-(4-bromophenyl)isoindole (4.0 gms.) is dissolved in 100 ml. of ethanol and oxidized by bubbling oxygen through the solution for 36 hours. The precipitated solid is separated by decantation and recrystallized from dimethylformamide. In this manner, is obtained 6-(4-bromophenyl)-2,3,4,6- tetrahydropyrimido[2,1-a]isoindol-6-ol, m.p. 278279C. dec., as a white crystalline solid which is insoluble in water and slightly soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 228 mp. (e=22,500), max. 267 my. (e=4,300); Ultra Violet Absorption (pH 1) max. 229 mp. ($21,500), max. 267 mu (e=4,300); Infra Red Absorption (KBr) 1645 cm", 2300-2900 cm.

Calcd for C H BrN O: C, 59.48; H, 4.41; N, 8.16.

Found: C, 59.51; H, 4.36; N, 8.26.

Similarly, utilizing anhydrous ethylene glycol dimethyl ether as the solvent. 6-(2,4-dibromophenyl)- 2,3,4,6-tetrahydropyrimido[2,l-a]isoindol-6-ol is synthesized. 5O

EXAMPLE V 2-(3-Aminopropyl)-l-(5,6,7,8-tetrahydro-2'- naphthyl)isoindole (3.0 gms.) is dissolved in 250 ml. of benzene and'oxidized by bubbling oxygen through the solution for 60 hours. The precipitate is separated by filtration and recrystallized from dimethylacetamide. In this manner, is obtained 6-(5,6,7,8-tetrahydro-2 naphthyl)-2,3,4,6-tetrahydropyrimido[2,l-alisoindol- 6-ol. mp. 25 3255C. dec., as a white crystalline solid which is insoluble in water and soluble in hot dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) infl. 230m (s=10,000), infl. 245 mu (e=9,200), max. 270 mu (=3,200); Ultra Violet Absorption (pHl infl. 230 mp. (e=10,900), infl. 245 mu (e=10,000), max. 270 mu (e=3,200); Infra Red Absorption (KBr) 1655 cm", 23003000 cm".

Calcd for C H N O: C, 79.21; H, 6.96; N, 8.80.

Found: C, 78.96; H, 7.15; N, 8.95.

In a similar manner, 6-(4-trifluoromethylphenyl)- 2,3,4,6-tetrahydropyrimido[2,l-a]isoindol-6-ol; 6-(2- trifluoromethylphenyl)-2,3,4,6- tetrahydropyrimido[2,1-a]isoindol-6-ol; and 6-furyl- 2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol are produced.

EXAMPLE VI Repeating the procedure of Example V but starting with 2-(3-aminopropyl)-l-methylisoindole, there is obtained 2,3,4.6-tetrahydro-6-methylpyrimido[2,1- a]isoindol-6-ol, m.p. 199201C., as a white crystalline solid which is insoluble in water and soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 236 mp. (F12,600), infl. 265 mp. (e=4,l); Ultra Violet Absorption (pHl) max. 239.5 mp. (e=l4,200), infl. 265 mu (e=4,100); Infra Red Absorption (KBr), 1640 cm, 2,3003,000 cm ,1nfra Red Absorption of the in situ hydrochloride salt by the procedure of Hofmann et al, Analyt, Chem. Vol. 39, pg. 406 (1967) (KBr) 1670 cm, 1647 cm", 2,600-3,l00 cm.

Calcd for C H N O: C, 71.26;H, 6.98 N, 13.87.

Found: C, 71.30; H, 6.90; N, 13;63

In a similar manner, the following compounds are prepared:

2.3,4.6-Tetrahydropyrimido[2,l-alisoindol-6-o1, m.p. 205-207C., as a white crystalline sold which is insoluble in water and slightly soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 235 mu (6 12.400). infl. 266.5 my. (e=3,650); Ultra Violet Absorption (pHl) max. 240 mp. (e=10,800), infl. 266.5 nm (e=3,650); Infra Red Absorption (KBr) 1640 cm, 2300-3000 cm ;1nfra Red Absorption of the in situ hydrochloride by the above-identified procedure (KBr) 1670 cm, 2.600-3,100 cm.

Calcd for C H N O: C, 70.18; H, 6.42; N, 14.88.

Found: C, 69.92; H, 6.47; N, 14.71.

6-Benzyl-2,3,4,6-tetrahydropyrimido[2,l-a]isoindol- 6-01, m.p. 233235C. dec., as a white crystalline solid which is insoluble in water.

Analysis: Ultra Violet Absorption (95% ETOH) max. 235 mp. (6 11.700), infl. 269 mp. (F3300); Ultra Violet Absorption (pHl) max. 240 mp. (e=l2,900), inf]. 269 mp. (e=3,900); Infra Red Absorption (KBr) 1645 cm, 2.3003,000 cm; Infra Red Absorption of the in situ hydrochloride by the above-indentified procedure (KBr) 1665 cm, 2.600-3,l00 cm".

Calc'd for C.,,H,,.N.,0; C, 77.66; H, 6.52; N, 10.07.

Found: C. 77.67; H, 6.41; N, 9.77.

o-Butyl-2,3,4,6-tetrahydropyrimido[2,1-a]isointlol- 6-o1, m.p. 18l-183C., as a white crystalline solid which is insoluble in water and soluble in ethanol and dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 234.5 my. (F12,100), infl. 266 mu (e=4,000); Ultra Violet Absorption (pHl) max. 240 mu (=14,000), infl. 266 mu (E=4,()00)', Infra Red Absorption (KBr) 1640 cm, 2,3003,0()0 cm; Infra Red Absorption of the in situ hydrochloride by the above-indentified procedure (KBr) 1670 cm, 1640 cm, 2,600-3,10O cm.

Calcd for C, H N O: C, 73.73; H, 8.25; N, 11.47.

Found: C, 74.03; H, 7.99; N, 11.63. 6-(3-Amino-4-chlorophenyl)-2,3,4,6-

tetrahydropyrimido[2,l -a]isoindol-6-ol,

227-228C. dec., as a white crystalline solid which is insoluble in water and soluble in hot dimethylacetamide.

Analysis: Calcd for C, H ,,C1N O:C, 65.05; H, 5.14;

methylacetamide.

Analysis: Calcd for c H N O: C, 77.67; H, 6.52; N,

Found: C, 77.62; H, 6.48; N, 9.94.

EXAMPLE V11 When the procedure of the aforementioned Examples is employed,

the hereinafter listed 2-(3- aminopropyl)phenyl-isoindoles are oxidized to afford the following products:

2-(3-AM1NOPROPYL) PHENYLISOINDOLES TETRAHYDROPYR1MlDO- ISOINDOLOLS 2-( B-aminopropyl )-6-chlorol phenylisoindole 2-( 3-aminopropyl-5-methyll-phenylisoindole 2-( 3-aminopropyl )-6-ethylamino- 1 he nylisoindole 2-( 3-aminopropyl)-5.6-dichlorol-phenylisoindole 2-(3-aminopropyl-5,-dimethoxyl-phenylisoindole 2(3-aminopropyl)-1-(3,4- diiodophenyhisoindole 2-( 3-aminopropyl 1 -isopropyl -5 ,6-dipropoxyisoindole 2-(3-aminopropyl)-1-( 3,4- diethoxyphenyhisoindole 2-(3-aminopropyl)-1-(4-hexylphenyl)isoindole 5-amino-2-( B-aminopropyl) isoindole 5-chloro-1-(4-ethylphenyl) isoindole 2-( 3-amin0propyl )-1-( 2- thienyhisoindole 2-( 3-aminopr0pyl)-5-methyll-phenylisoindole 2-( 3-aminopropyl1-1-phcny1- 7-propylisoindole 2-( 3-aminopropyl)- l 4-11uorophcnyl )isoindole 2-( 3-aminopropyl 1 3-bromo- 4-methylphenyl )isoindole 2-(3-aminopropy1l- 1 -(3-iodophcnyl )isoindolc 2-( 3-aminopropylj-5-umyl-1- phenylisoindole 2-( 3-aminopropyl 1 -phcnyl- 6-propylaminoisoindolc 2-(3-aminopropyl)-5-butoxyl-phenylisoindole 8-chloro-2,3,4,6-tctrahydro- 6-phenylpyrimido[2.1-a] isoindo1-6-o1 2,3,4,6-tet'rahydro-9-methyl- 6-pheny1pyrimido[2. 1 -a] isoind 01-6-01 8-ethylamino-2,3,4,6-tetrahydro- 6-phenylpyrimido 1 2, 1 a] isoindol-6-ol 8,9-dichloro-2,3,4,6-tetrahydro-6-phenylpyrimido[2, l-a] isoindol-G-ol 2,3,4,6-tetrahydro-8,9- dimethoxy-6-phenylpyrimido [2,1-a1isoindol-6-ol 2,3,4,6-tetrahydro-6-(3,4- diiodophenyhpyrimidol 2,1-a] isoindol-6-ol 2,3,4,6-tetrahydro-6-isop ropyl -8,9-dipropoxypyrimido[2,1-a] isoind 01-6-01 6-( 3,4-diethoxyphenyl-2,3,4,6 -tetrahydropyrimido[2. 1 -a] isoinclol-6-ol 6-(4-hexylphenyl )-2,3,4,6- tetrahydropyrimidolZ, 1 -a] isoindol-6-ol 9-amino-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol- 6-01 9-ch1oro-6-(4-ethylphenyl)- 2,3,4,6-tetrahydropyrimido [2.1-a1isoindol-6-ol 2,3,4,6-tetrahydro-6- (2-thienyl1pyrimidol2, 1 -21] isoindo1-6-ol 2,3,4,6-tetrahydro-9-methyl- 6-phenylpyrimido[ 2, l -a] isoindol--ol 2,3,4,6-1etrahydro-6-phenyl- 7-propylpyrimido[ 2,1-a] isoindol-6-ol 6-(4-11 uorophcnyl )-2,3,4 ,6- tetrahydropyrimido12,l-al isoindol-6-ol 6-( 3-bromo-4-methylphenyl 2,3 ,4,6-tetrahydropyrim ido [2, l -a lisoindol-b-ol 2,3,4,6-tctrahydro-6-(3- iodophenyl )pyrimido[ 2, l-a] isoindol-6-ol 9-amy1-2,3,4,6-tctrahydro- 6-pheny1pyrimido12, l-a isoindol-(vol 2,3,4,6-tctrahydro-6-phcnyl- 8-propylaminopyrimidol 2,1-a] isoindol-fi-ol 9-butoxy-2.3.4,6-tetrahydro- 6-phen ylpyrimido[ 2, l -a] isoindol-o-ol -Cntinued TETRAHYDROPYRIMIDO ISOINDOLOLS 2-(3-AMINOPROPYL) PHENYLISOINDOLES 234,6 -tetrahydro-6 3,4- dimethylphenyUpyrimido [2, 1 -21 ]isoindol-6-ol 2,3,4,6-tetrahydro-6-(4- propoxyphenyl)pyrimido [2.I-a1isoindol-6-ol 2,3,4,6-tetrahydro-8,9 dimethylpyrimido[ 2, l -a] isoindol--ol 2,3,4,6-tetrahydro-6- pyridylpyrimido[ 2. [-21] isoindol--ol 6-butyl-2,3.4,6-tetrahydro- 9methoxypyrimido[ 2, I -a] isoindol-6-ol 2-( 3-aminopropyl l -(4-propoxyphcnyl )isoindolc 2-( 3aminopropyl )-5,6- dimethylisoindole 2-( 3-aminopropyl I -pyridylisoindole 2-( 3-aminopropyl I -butyl-5 -methoxyisoindole EXAMPLE VIII Ten grams of 2,3 ,4,6-te trahydro-6-( 2- thienyl)pyrimido[2,l-a]isoindol-6-ol, as described in Example VII, are suspended in 75 ml. of absolute ethanol and then saturated with a continuous flow of hydrochloric acid gas. The resulting solution is evaporated to dryness and ethanol-ethylacetate to yield 234,6- tetrahydro-6-(2-thienyl)pyrimido[2,l-a]isoindol-6-ol hydrochloride, mp. 238C. dec., as a white crystalline solid which is soluble in water.

Analysis: Calcd for C H N OSIICl: C, 58.71; H,

4.93; N, 9.14; CI, 11.56; S, 10.45 Found: C, 58.77; H, 4.74; N, 9.20; Cl, 11.75; S, 10.8.

Example IX When the procedure of Example VIII is repeated with the tetrahydropyrimidoisoindolols of Examples II VII, the following respective hydrochloride salts are obtained:

8-bromo-2,3,4,6-tetrahydro-6-(4- tolyl)pyrimido[2,l-a]isoindol-6-ol hydrochloride;

2-(3,4,5,-tetrahydro-Z-pyrimidinyl)-4- methylbutyrophenone hydrochloride;

2-(3,4,5,6-tetrahydro-2-pyrimidinyl)-3- iodobenzaldehyde hydrochloride;

8,9-dibromo-6-(4-bromophenyl)-2,3,4,6- tetrahydropyrimido[2,l-a]isoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-6-(2,4-dimethoxyphenyl)- pyrimido [2,l-a1isoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-6-phenylpyrimidol2,l-a]isoindol- 6-ol hydrochloride;

6-(3,4-dichlorophenyl-2,3,4,6- tetrahydropyrimido[2,l-a]isoindol-6-ol hydrochloride;

6-( 4-bromophenyl )-2 ,3 ,4 ,6-tetrahydr0pyrimido[ 2, l

16 6-( 3-amino-4-chlorophenyl )-2,3.4,6-

tetrahydropy rimido[ 2, l -a isoindol-o-ol hydrochloride;

2,3 ,4,6-tetrahydro-6-( 4-tolyl )pyrimido 2, l a]isoindol-6-ol hydrochloride;

8-chloro-2 ,3 ,4,o-tetrahydro--phenylpyrimido[ 2. l

. a]isoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-9-methyl-o-phenylpyrimido[2,I- a]isoindol-6-ol hydrochloride;

8-ethylamino-2,3,4,6-tetrahydro-6 phenylpyrimido[2,l-a]isoindol6-ol dihydrochloride;

8,9-dichloro-2,3,4,6-tetrahydro-6-phenylpyrimido [2,l-a]isoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-8,9-dimethoxy--phenylpyrimido [2,l-alisoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-6-(3,4-diiodophenyl)pyrimido [2,l-a]isoindol-6-ol hydrochloride;

2-(3,4,5,6-tetrahydro-2-pyrimidinyl)-2-methyl-4,5- dipropoxypropiophenone hydrochloride;

6-(3,4-diethoxyphenyl)-2,3,4,6-tetrahydropyrimido [2,l-a]isoindol-6-ol hydrochloride;

6-(4-hexylphenyl)-2,3,4,6-tetrahydropyrimido[2,1- a]isoindol-6-'ol hydrochloride;

4-amino-2-(3,4,5,6-tetrahydro-2- pyrimidinyl)benzaldehyde dihydrochloride;

9-chloro-6-(4-ethylphenyl) 2,3,4,6- tetrahydropyrimido[2. l -a]isoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-6-(Z-thienyl)pyrimido[2,1- a]isoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-9-methyl-o-phenylpyrimido[ 2. l a]isoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-6-phenyl-7-propylpyrimido[ 2, I a]isoindoI-6-ol hydrochloride;

6-(4-fluorophenyl)-2,3,4,6-tetrahydropyrimido[2,la]isoindol-6-ol hydrochloride;

6-(3-bromo-4-methylphenyl)-2,3,4,6- tetrahydropyrimido[2,l-a]isoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-6-(3-iodophenyl)pyrimido[2,lalisoindol--ol hydrochloride;

9-amyl-2,3,4,6-tetrahydro-6-phenylpyrimido[2,lalisoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-6-phenyl-8- propylaminopyrimido[2,l-a]isoindol-6-ol chloride;

9-butoxy-2,3,4,6-tetrahydro-6-phenylpyrimido[2,lalisoindol-o-ol hydrochloride; 2,3,4,6-tetrahydro-6*( 3,4-

dihydrodimethylphenyl )pyrimido[2, l -a]isoindol-6-ol hydro chlorides;

2,3 ,4,6-tetrahydro-6-( 4- propoxyphenyl)pyrimido[2,]-a]isoindol-6-ol hydrochloride;

2-(3,4,5,6-tetrahydro-2-pyrimidinyl)-4,5-dimethylbenzaldehyde hydrochloride;

2,3,4,6-tetrahydro-6-pyridylpyrimido[2,l-a]isoindol- 6-ol hydrochloride; and

2-(3,4,5,6-tetrahydro-2-pyrimidinyl)-4- methoxyvalerophenone hydrochloride.

Example X Thirty-five grams of 9b-(p-chlorophenyI)-l,2,3,9btetrahydro-lH-imidazo[2,l-a]isoindol-5-one and I50 ml. of percent hydrochloric acid are stirred and heated to a clear solution. Stirring is continued for 20 minutes after solid begins to precipitate. The mixture is cooled and the solid is separated by filtration. On recrystallization from ethanol there is obtained 2-(2- aminoethyl)-3-(p-chlorophenyl)-3- hydroxyphthalimidine hydrochloride, m.p. 2435C.

Ten grams of 9b-(p-chlorophenyl)-l,2,3,9btetrahydrol -(p-tolylsulfonyl )-l H-imidazo[2, l a]isoindol--one are dissolved in ml. of 90 percent sulfuric acid and stirred at room temperature for hour. The solution is quenched with ice water, then filtered to separate some precipiated solid. The filtrate which contains the sulfate salt of 4'-chloro-2-(2- imidazolin-Z-yl)benzophenone is cooled and made basic with a saturated sodium bicarbonate solution. The precipitated solid is separated by filtration and washed thoroughly with water. On recrystallization from ethanol there is obtained 5-(4-chlorophenyl)-2,3- dihydro-5H-imidazo[2,la]isoindol-5-ol, m.p. 2l5-2l7C., dec., as a white crystalline solid which is insoluble in water and soluble in ethanol.

Analysis: Ultra Violet Absorption (95% ETOH) max. 223 mu (e=l9,000), infl. 242.5 mu (e=8,300), max. 268.5 m,u. (2 1.400), max. 272 mp. (e=4,400); Ultra Violet Absorption (pH 1) infl. 223 mu (e=l8,000), max. 251 mp. (e=l 1,000), max. 253 my. (e=l(),800); Infra Red Absorption (KBr) 1647 cm, 2,3003,20O cm".

Calcd for C H N OCl: C, 67.49; H, 4.60; N, 9.40;

Found: C, 67.18; H, 4.32; N, 9.68; Cl, 12.7.

In a similar manner, the sulfate salts of 2-(2- imidazolin-2-yl)-3',4-diiodobenzophenone; 2-(2- imidazolin-2-yl)-2-methyl-4',5'-dipropoxypropiophenone and 3,4-diethoxy-2-(2-imidazolin-2- yl)benzophenone are produced which are then contacted with a saturated sodium bicarbonate solution to respectively afford the following compounds: 2,3- dihydro-5-(3,4-diiodophenyl)-5H-imidazo[2,lalisoindol-S-ol; 2,3-dihydro-5-isopropyl-7,8- dipropoxy-5H-imidazo[2,l-a]isoindol-5-ol; and 5-(3,4- diethoxyphenyl)-2,3-dihydro-5H-imidazo[2,la]isoindol-5-ol.

Example Xl Seventy grams of 9b-(p-t0lyl)-l,2,3,9b-tetrahydrolH-imidazol2,1-a1isoindol-5-one and 300 ml. of 48 percent hydrobromic acid are stirred and heated to a clear solution. Stirring is continued for IS minutes after precipitation. Thereafter, the reaction mixture is cooled and the precipitated solid, 2-(2-aminoethyl)-3- (p-tolyl)-3-hydroxyphthalimidine hydrobromide, is separated by decantation, admixed with 40 g. of ptoluenesulfonyl chloride and 400 ml. of pyridine, heated to 100C. for 4 hours and evaporated to dryness.

Twenty grams of the residue 9b-(p-tolyl)-1,2,3,9b' tetrahydro-l-(p'tolylsulfonyl)-lH-imidazo[2,l-

a]isoindol-5-one are dissolved in 50 ml. of 80 percent sulfuric acid and stirred at room temperature for one hour. The reaction mixture which contains the sulfate salt of 2-(2-imidazolin-2-yl)-4-methylbenz0phenone is then cooled by the addition ofice water and made alkaline by the addition of a lON sodium hydroxide solution. The precipitated solid is separated by decantation and recrystallized from dioxan to obtain crystalline 2,3- dihydro-5-(4-tolyl)-5H-imidazo[2,l-alisoindol-S-ol, m.p. 208-210C.

In a similar manner, the following sulfates are synthesized: 4-hexyl-2-(2-imidazolin-Z-yl)benzophenone; 4- amino-2-(2-imidazolin-2-yl)benzaldehyde; 4-chloro- 2'-(2-imidazolin-2-yl)-2-phenylacetophenone; and 2- (2-imidazolin-2-yl)phenyl-2-thienyl ketone which are then contacted with a base to respectively afford the following: 5-(4-hexylphenyl)2,3-dihydro-5H- imidazo[2,l-a]isoindol-5-ol; 8-amino-2,3-dihydro-5H- imidazo[2,l-a]isoindol-5-ol; 8-chloro-5-(4- ethylphenyl)-2,3-dihydro-5H-imida20[2,l-a]isoindol- 5-ol; and 2,3-dihydro-5-(2-thienyl)-5H-imidazo[2,la]isoindol-5-ol.

Example Xll Thirty-five grams of 9b-phenyl-l,2,3,9b-tetrahydrolH-imidazo[2,l-a]isoindol-5-one and 150 ml. of 50 percent hydrochloric acid are stirred and heated to a clear solution. Stirring is continued for 30 minutes after solid begins to precipitate. The mixture is cooled and the solid is separated by filtration. On recrystallization from ethanol there is obtained 2-(2-aminoethyl)-3- phenyl-3-hydroxyphthalimidine hydrochloride.

Seventeen grams of the phthalimidine hydrochloride from above, 20 g. of p-butoxyphenylsulfonyl chloride and 200 ml. of pyridine are refluxed for 2 hours and then the mixture is evaporated to dryness. On recrystallization of the residue from ethanol there is obtained 9b-phenyl-l,2,3,9b-tetrahydro-l-(pbutoxyphenylsulfonyh-lH-imidazo[2,l-alisoindol- 5-one which is admixed with 25 ml. of percent sulfuric acid for 1 hour. The reaction mixture which contains the sulfate salt of 2-(2-imidazolin-2-yl) benzophenone is then cooled by the addition of ice water and made alkaline by the addition of a 5N potassium hydroxide solution. The product is then separated by filtration and recrystallized from dioxane to afford 2,3- dihydro5-phenyl-5H-imidazo[2,1-a]isoindol-5-ol, mp. 207C, as a white crystalline solid which is insoluble in water and soluble in dimethylacetamide and ethanol.

Analysis: Ultra Violet Absorption (95% ETOH) infl. 225 mu (e=l4,900), max. 268 mp. (e=4,200); Ultra Violet Absorption (pH 1) max. 250 mp. (Fl3,500);1nff21 Red Absorption (KBr) 1,660 cm", 2,300-3,000 cm.

Calcd for C H N O: C, 76.77; H, 5.63; N, 11.20.

Found: C, 76.63; H, 5.66; N, 110.

Similarly, the sulfate salts of 2-(2-imidazolin-2-yl) 4- methylbenzophenone and 2-(2-imidazolin-2-yU-6- propylbenzophenone are produced which are then converted to a 2,3-dihydro-8-methyl-5-phenyl-5H- imidaz0[2,l-alisoindol-S-ol and 2,3-dihydro-5-phenyl- 6-propyl-5H-imidazo[2,l-a]isoindol-5-ol.

Example Xlll Forty grams of 9b-(p-bromophenyl)1,2,3,9b-

tetrahydro-lH-imida2o[2,l-a]isoindol-5-one and 200 ml. of 50 percent hydrochloric acid are stirred and heated to a clear solution. Stirring is continued for 20 minutes after solid begins to precipitate. The mixture is cooled and the solid is separated by filtration. On recrystallization from ethanol there is obtained 2-(2- aminoethyl)-3-(p-bromophenyl)-3- hydroxyphthalimidine hydrochloride.

Twenty grams of the phthalimidine hydrochloride from above, 24 g. of p-bromophenylsulfonyl chloride and 250 ml. of pyridine are refluxed for 3 hours and then the mixture is evaporated to dryness. On recrystallization of the residue from methanol there is obtained 9b-(p-bromophenyl)-l ,2,3 ,9b-tetrahydrol -(pbromophenylsulfonyl )-l H-imidazo[2, l -a]isoindol- S-one which is hydrolyzed with sulfuric acid to afford the sulfate salt of 4'-bromo-2-(2-imidazolin-2- yl)benzophenone which is contacted with an aqueous sodium hydroxide solution. The product is then separated by filtration to afford 5-(4-bromophenyl)-2,3- dihydro-5H-imidazo[2,1-a] isoindol-S-ol, m.p. 194-196C., as a white crystalline solid which is soluble in dimethylacetamide and hot ethanol.

Analysis: Ultra Violet Absorption (95% ETOH) max. 228 mp. (e=l5,300), max. 268 mp. (e=4,800), max. 274 my. (e=4,800); Ultra Violet Absorption (pH 1) max.-250 mp. (e=ll,000), max. 270 my. (e=10,500); Infra Red Absorption (KBr) 1660 cm, 2,3003,000 cm.

Calcd for C H N OBrz C, 58.38; H, 3.98 N, 8.50;

Found: C, 58.25; H, 4.02; N, 8.46; Br, 24.00.

In a similar manner, the following compounds are prepared:

3,4'-dichloro-2-(2-imidazolin-2-yl)benzophenone sulfate which is neutralized to afford 5-(3,4- dichlorophenyl)-2,3-dihydro-5H-imidazo[2,lalisoindol-S-ol, m.p. 203-205C., as a white crystalline solid which is soluble in hot dimethylacetamide and hot ethanol.

Analysis: Ultra Violet Absorption (95 /o ETOH), infl. 228 mp. (e=2l,200), max. 274 mu (e=4,500), max. 281 mu (e=3,500); Ultra Violet Absorption (pH 1 max. 243 mu (Fl2,200), max. 251 mu (E=l 1,750), infl. 265 mp. (FQDOO), infl. 278 my. (e=6,750); Infra Red Absorption (KBr) 1655 cm, 2,3003,000 cm.

Calcd for C16H 2Cl2N-lO: C, 60.21; H, 3.79; N, 8.78;

Found: C, 59.91; H, 3.66; N, 8.66; Cl, 22.30.

4'-fluoro-2(2-imidazolin-2-yl)benzophenone sulfate which is neutralized to afford 5-(4-fluorophenyl)- 2,3dihydro-5 H-imidazo[2,1-a]isoindol-5-ol, m.p. 214216C., dec., as a white crystalline solid which is insoluble in water and soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH), infl. 235 mu (e=l2,000), infl. 242 my. (e=l0,200), max. 263 Ill/.L (e=6,l), max. 268 mu (e=5,600); Ultra Violet Absorption (pH 1) max. 251 (e=l 3,000);lnfra Red Absorption (KBr) 1640 cm", 2,3003,000 cm".

Calcd for C H N OF: C, 71.62; H, 4.88; N, 10.44.

Found: C, 71.73; H, 5.00; N, 10.68.

3'-bromo-4'-methyl-2-(Z-imidazolin-Z- yl)benzophenone sulfate which is neutralized to afford -(3-bromo-4-methylphenyl)-2,3-dihydro5H- imidazo[2,l-a]isoindol-5-ol, m.p. 2332 35C., dec., as a white crystalline solid which is insoluble in water and soluble in dimethylacetamide.

Analysis: Calcd for C H BrN O: C, 59.47; H, 4.41;

N, 8.16; Br, 23.28. Found: C, 59.75; H, 4.60; N, 8.32; Br, 23.23.

Example XlV Ninety grams of l,2,3,9b-tetrahydro-9b-phenyl-5H- imidazo[2, 1 -a]isoindol-5-0ne, g. of ptoluenesulfonyl chloride and 1 liter of pyridine are heated at reflux for 14 to 18 hours. The solution is evaporated in vacuo to dryness, the residue slurried with water and then separated by filtration. On recrystallization from ethanol there is obtained g. of 9bphenyll ,2,3,9b-tetrahydrol -(p-tolysulfonl 5H- imidazo[2,1-a]isoindol-5-one, m.p. l58-l60C.

Ninety grams of the above prepared sulfonamide compound is dissolved in 200 ml. of 80% sulfuric acid and is left at room temperature for 2 hours. The solution is diluted with two volumes of water and extracted with ether. The aqueous portion which contains the sulfate salt of 2-(2-imidazolin-2-yl)benzophenone is then neutralized with 50% sodium hydroxide solution while keeping the temperature below 25C. The solid is separated and washed with water. On recrystallization from dimethylformamide there is obtained 27 g. of 2,3- dihydro-S-phenyl-5H-imidazo [2,l-a]isoindol-5-ol which has the same analytical characteristics as the product of Example Xll.

Example XV Sixty grams of 9b-(4-chlorophenyl)-l,2,3,9btetrahydro-5H-imidazo[2,1-a]isoindo|-5-one, 60 g. of p-toluenesulfonyl chloride and 750 ml. of pyridine are heated at reflux for 14 hours. The reaction mixture is worked-up as described in Example XlV to obtain 70 g. of 9b-(p-chlorophenyl)-l,2,3,9b-tetrahydro-l-(ptolylsulfonyl)-5H-imidazo [2,1-a]isoindol-5-one, m.p. 169-l71C. which can be recrystallized from ethanol (m.p. 170172C.).

Forty-five grams of the above prepared sulfonamide compound is dissolved in ml. of 80% sulfuric acid and is left at room temperature for 2 hours. The solution is diluted with two volumes of water and extracted with ether. The aqueous portion which contains 4'- chloro-2-(2-imidazolin-2-yl)benzophenone is neutralized with 50% sodium hydroxide solution while keeping the temperature below 25C. The solid is separated, washed with water and recrystallized from dimethylformamide to afford 23 g. of 5-(4-chlorophenyl)-2,3- dihydro-5H-imidazo[2,l-alisoindol-S-ol which has the same analytical characteristics as the product of Example X.

The above procedure is repeated to react a 1,2,3,9btetrahydro-lH-imidazo[2,l-a]isoindol-5-one of V1"- -Xll with an appropriate sulfonyl halide, in pyridine, at a temperature within the range of about 80C. to above C. for a period of about 2 to about 10 hours to afford the corresponding sulfonamide which is treated with about 80 to about 100 percent sulfuric acid to yield an appropriate 2 (2-imidazolin-2- yl)benzophenone sulfate which is neutralized to produce a 2,3-dihydro-5H-imidazo[2,l-a] isoindol-S-ol.

EXAMPLE XVl Ten grams of 2,3-dihydro-5-phenyl5H-imidazo[2,1- a]isoindol-5-ol, as described in Example Xll, are suspended in 75 ml. of absolute ethanol and then saturated with a continuous flow of hydrochloric acid gas. The resulting solution is filtered to remove impurities and on standing 2-(2-imidazolin-2-yl)benzophenone hydrochloride precipitates as a white crystalline sold, m.p. I97I99C., dec.

Analysis: Ultra Violet Absorption (95% ETOH) max. 250 my. (e=l2,800); Infra Red Absorption (KBr) 1647 cm", 2,400-3,200 cm".

Calcd for C H N O.HCl: C, 67.03; H, 5.27; N,

9.77; CI, 12.36. 7 Found: C, 66.88; H, 5 .33; N, 9.83; Cl, l2.50.

EXAMPLE XVII Ten grams of 5-(4-chlorophenyl-2,3-dihydro-5H- imidazo[2,l-a]isoindol-5-ol, as described in Example X, are suspended in 75 ml. of absolute ethanol and then saturated with a continuous flow of hydrochloric acid gas. The resulting solution is filtered, evaporated to dryness and the residue recrystallized from ethanolethyl acetate to afford 4'-chloro-2-(2-imidazolin-2l -yl)benzophenone hydrochloride. m.p. l70-172C., dec., as a white crystalline solid which is soluble in water.

Analysis: Ultra Violet Absorption (95% ETOH) infl. 223 mp. (e=l9,l00), max. 252 mp. (FIZJOO), max. 265 mu (Fl2,300); Infra Red Absorption (KBr) 1647 cm, 2,300-3,200 cm.

Calcd for C H, N OCl.HCl: C, 59,80; H, 4.40; N,

Found: C, 59.63; H, 4.50; N, 8.72; Cl, 21.79.

Similarly, the following hydrochlorides are prepared:

2-(2-imidazolin-2-yl)-3,4'-diiodobenzophenone hydrochloride;

2-(Z-imidazolin-Z-yl)-2-methyl-4,5'-dipropoxypropiophenone hydrochloride;

chloride;

4-bromo-2-(2-imidazolin-2-yl)benzophenone hydrochloride;

3',4'-dichloro-2-(2-imidazolin-2-yl)benzophenone hydrochloride;

4'-fluoro-2(2-imidazolin-2-yl)benzophenone hydrochloride; and

3'-bromo-2-(2-imidazolin-2-yl)-4- methylbenzophenone hydrochloride.

EXAMPLE XVIII When the procedure of Examples X XV are repeated with appropriate starting material, the following dihydroimidazoisoindolols are prepared which by the procedure described in Examples XVI XVII are then converted to their corresponding imidazolinyl phenyl carbonyl hydrochlorides.

DlHYDROlMIDAZOISOINDOLOLS 2,3-dihydro8methyl-S-propyl- SH-imidazol 2. 1 -a]isoindol-5-ol 2,3-dihydro-9-iodo-5H-imidazo [2,l-a1isoindol-5-ol 7,8-dibromo-5-( 4-bromophenyl 2,3-dihydro-5H-imidazo[ 2, I -a] isoindol-5-ol isoindol-S-ol 5-(2,4-dibromophen l)-2,3- dihydro-SH-imidazo 2,l-a]

isoindol-S-ol 2,3-dihydro-5-(5,6,7,8-tetrahydro -2-naphthyl )-5 H -imidazo[ 2, l -a] isoindol-S-ol isoindol-S-ol isoindoI-S-ol isoindo S-benzyl-Z,3-dihydro-5H-imidazo [2, I -21 lisoindol-S-ol 5-hutyl-2.3-dihydro-SH-imidazo [2, l -a]isoindol-5-ol 5-( 3-amino-4-chlorophcnyl )2,3- dihydro-SH-imidazol 2, I -ulisoindol-S-ol S-brom o2-( 2-imidazolin- 2yll-4-methylbenzophenone hydrochloride 2-( Z-imidazolin-Z-yl )-4- methylbutyrophenone hydrochloride 2-(2-imidazolin-2-yl)-3 iodobenzaldehyde hydrochloride 4.4.5-tribromo-2-(2- imidazolin-2 yl)benzophenone hydrochloride 2-(2-imidazolin-2-yl)-2',4' dimethoxybenzophenone hydrochloride 2',4"dibromo-2-(Z-imidazo- Iin-Z-yIJbenzophenone hydrochloride Z-(Z-imidazolin-Z-yl) phenyl-(5,6,7,8-tetrahydro -2-naphthyl)ketone hydrochloride 4'-trifluoromethyl-2- (2-imidazolin-2-yl)benzophenone hydrochloride 2'-trifluoromethyl-2-(2- imidazolin-Z-yl)benzophenone hydrochloride furyI-Z-(Z-imidazolin)-2-yl) phenyl ketone hydrochloride 2-( 2-im idazoIin-Z-yl )ace tophenone hydrochloride 2-( 2-imidazolin-2-yl )benzaldehyde hydrochloride 2-(2-imidazolin-2-yl)-2- phenylacetophenone hydrochloride 2-( 2-imidazolin-2-yl )valcrophenonc hydrochloride 3'-amino'4'-chloro-2-( 2- imidazolin-Z-yl)benzophenonc dihydrochloride Continued DlilYDROlM lDAZOlSOlNDOLOLS lMlDAZOLlNYL PHENYL CARBONYL HYDROCHLORIDE 7-chloro-2,3-dihydro-5-phenyl- 5 H-imidazo[ 2v 1 -a]isoindol-5-ol 2,3-dihydro-B-methyl-S-phenyL SH-imidazol 2, l -a]isoindol-5-ol 7-cthylamino-2.3-dihydro-5- phenyl-SH-imidazol 2, l-a] isoindol-S-ol 7,8-dichloro-Z.3-dihydro-5- phenyl-5 H-imidazol 2. l -a] isoindol-S-ol 2.3-dihyd ro-7,8-dimcthoxy-5- phcnyl'5 H-imidazol 2, l a] rsoindol-S-ol 2,3-dihydro-5( 3-iodophenyl 5H-imidazo[ 2. l -a lisoindol-S- ol S-umyl-2.3-dihydro-5-phenyl- 5H-imidazo[ 2,1 a]is0indol-5 ol 2.3-dihydro-5 phenyl-7-propyl- 5H-imidazo[ 2, l -a lisoindoLS-ol ll-hutoxy-Z.3-dihydro-5phcnyl- SH-imidazol 2.1 -ulisoindol-5-ol 2.3-tlih \'dro-5-( 3.4-dinicthylphenyl l 5H-imiduzo[ 2. l -11] isoindoLS-ol 2.3-dihydro'5-( 4-propoxyphenyl )-5H-imitluzo| 2. l -a| isoindol-S-ol I.J-dihydroJfi'dimethyI SH- iniidazol2.l-a1isoindol-5-ol 5-chloro-2-(Z-imidazolin- 2-yl)benzophenone hydrochloride 2-(2-imidazolin-2-yl)-4- methylbenzophenone hydrochloride 5-ethylamino-2-(Z-imidazolin -2-yl)benzophenone dihydrochloride 4,5-dichloro-2-(Z-imidazolin 2-yl )bcnzophenone hydrochloride 2-( Z-imidazolin-Z-yl )-4,5 dimethoxybenzophenonc hydrochloride 2( 2-im idazolin-Z-yl )-3 iodobenzophenone hydrochloride 4-amyl-2-(Z-imidazolin-Z-yl) benzophenone hydrochloride 2-( 2-im idazolin-2-yl )-5- propylbenzophenone hydrochloride 4'butoxy-2-(2-imidazolin-2-yl) benzophenone hydrochloride 2-( Z-im idazolin-Z-yl )-3',4'- dimcthylbenzophenonc hydrochloride propoxybcnzophenone hydrochloride 2-( Z-imidazolin-Z-yl )-4,5 dimeth ylbenzaldehyde h ydrochloride EXAMPLE XIX Z-(Z-Imidazolin-Z-yl)benzophenone hydrobromide is prepared by admixing an ethanolic solution of 2,3- dihydro-5-phe nyl-5H-imidazo[2,1-a]isoindol-5-ol with an ethanol solution containing an equivalent amount of hydrobromic acid and, thereafter, evaporating the solvent under vacuum.

Other new tetrahydropyrimidinyl phenyl carbonyl imidazolinyl phenyl carbonyl and tetrahydropyrimidoisoindolol acid addition salts of the present invention are prepared by the same procedure employing hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, maleic acid and gluconic acid.

EXAMPLE XX l-(p-chlorophenyl )-l ,2,3 ,4,5 ,6-

dihydrochloride are Two grams of hexahydro-2,5-benzodiazocine EXAMPLE XXI Repeating the procedure of Example XX to oxidize a hereinafter listed hexahydrobenzodiazocine, the following dihydroimidazoisoindolol compounds are predissolved in 50 ml. ofwater. A solution of l g. of potas- 50 pared:

HEXAHYDROBENZODIAZOCINE l ,2, ,5.6-hexahydi-Q-1.( p y )-2,5benzodiazo- DlHYDROlMlDAZOlSOlNDOLOLS 5-(4-bromophenyl-2,3-dihydro- 5H-imidazo[ 2,l-a]isoindolcine dihydrochloride 5-01 l,2,3.4,5,6-hexahydro-l-(pmethoxyphenyl )-2,5-benzodiazocine dihydrochloride l-benzyll ,2,3 ,4,5 ,6-hexahydro-2,5-benzodiazocine 2,3-dihydro-5-(4-methoxyphenyl )-5H-imidazo[ 2, l -a] isoindol- 5-ol 5-benzyl-2,3-dihydro-5 H- imidazo[ 2, l -a]isoindol-5-ol dihydrobromide l ,2,3 ,4,5,6-hexahydro-l-(2- thien l)-2.5-benzodiazocine dihy rochloride l-(3-furyl)-l .2,3 .4,5,6- hexahydro-Z,S-benzodiazocine dihydrochloride 2.3-dihydro-5-(2-thienyl)- gH-limidazon.l-alisoindol- Continued HEXAHYDROBENZODIAZOCINE DIHYDROIMIDAZOISOINDOLOLS I j;.3,4.5.6-hexahydro-8.9 dimethoxyl p-tolyl )-2.5- bcnzodiazocinc dihydrochloride 2,3-dihydro--(2-pyridyl)- 5H-imidazol2. l-alisoindol- S-ol 2.3-dihydro-7.8-dimethoxyisoindol-S-ol EXAMPLE XXll Four grams of l,2.3.4,5,6-hexahydro-8,9-dimethyl-lphenyl-2,S-benzodiazocine is dissolved in 100 ml. of acetone. A solution of 2 g. of potassium chlorate in lOO ml. of water is added dropwise over a period of an hour.

EXAMPLE XXIV When the oxidation procedures of the previous Examples are repeated at temperature ranges from C. to 60C. for periods of up to about 4 hours on the following hexahydrobenzodiazocines the hereinafter Thereafter, the mixture is filtered and evaporated to 20 listed dihydroimidazoisoindolol compounds are obdryness to afford 2,3-dihydr0-7,8-dimethyl-5H- tained:

HEXAHYDROBENZODIAZOCINES DIHYDROIMIDAZOISOI NDOLOLS l.2.3.4.5.6-hcxahydro- 1 5 .6- 7.8-tctrahydro-Z-naphthyl 2.5-benzodiuzocine l.2.3.4.5.6-hexahydrol ptrit'luoromethylphcnyl)-2.5- benzodiazocine l.2.3.4.5.6-hexahydro-8.9 dichlorol -phenyl-2.5- hcnzodiazocine l-( p-ethylphenyl 1 13.4- 5.6 hexahydro-2.5-henzodiazocine 8.9'dibromo-l .2 .3,4.5.6- hexahydrol '-phenyl-2,5- benzodiazocine l.2,3.4.5,6'hexahydro-9- methylaminol -(p-tolyl)- 2.5-benzodiazocine dihydro-S H -imidazo[ 2, l -a ]isoindol-5-o|.

EXAMPLE XXIII One gram of l,2,3,4,5,6-hexahydro-l-phenyl-2,5- benzodiazocine dihydrochloride is dissolved in ml. of water. A solution of 0.5 g. of potassium permanganate in 25 ml. of water is added over a period of 1 hour. The mixture is filtered to remove precipitated inorganic salts and the filtrate is made alkaline with a potassium bicarbonate solution. The precipitated product is separated and recrystallized from ethanol. The product obtained in this manner is 2,3-dihydro-5-phenyl-5H- imidaz0[2.l-a]isoindol-5-ol which has the same physical characteristics as the identical compound of Example Xll.

In the same manner, l,2,3.4,5.6-hexahydro-l-(2,4- dimethoxyphenyl)-2,5-benzodiazocine is converted to 2.3-dihydro5-(2.4-dimethoxyphenyl)-5H- imitlazol 2.1 -u lisoindol-S-ol.

2.3-dihydro-5-(5.6,7,8- tctrahyd ro-2-naphthyl J5H imidazol 2.1 11 lisoindol-S-ol 5-t 4-tritluoromethylphcnyl 2.3-dihydro-5Himidazo [2. l -a]isoindol-5-ol 7.8-dichlore-2.3-dihydro- 5-phenyl-5H-imidazo[ 2. l -a] isoindol-5ol 4 5-(4-ethylphenyl )-2.3dihydro-5H -imidazo[ 2. l -a] isoindol-S-ol EXAMPLE XXV Ten grams of l-(3,4-dichlorophenyl)-l 23.4.5.6- hexahydro-2,S-benzodiazocine dihydrochloride are dissolved in 250 ml. of water. A solution of 5.0 g. of p0- tassium permanganate in 250 ml. of water is added over a period of 2 hours. The mixture is filtered to remove precipitated inorganic salts and the filtrate is made alkaline with a sodium bicarbonate solution. The precipitated product is separated and recrystallized from methanol. The product obtained in this manner is 5- (3,4-dichlorophenyl)-2,3-dihydro5H-imidazo[2, l a]isoindol-5-ol which has the samephysical characteristics as the identical compound of Example XIll.

Similarly, l-(3,4-dibromophenyl)-l,2.3,4,5,6- hexahydro-9-methyl-2,5-benzodiazocine dihydrobromide is oxidized to afford 5-(3,4-dibromophenyl)-2.3- dihydro-S-methyl-5H-imidazo[2,l-a]isoindol-5-ol.

EXAMPLE XXVI When the oxidation procedure of Examples XX to XXV is repeated employing the following hexahydrobenzodiazocines as starting materials, the hereinafter listed dihydroimidazoisoindolol compounds are produced.

HEXAHYDROBENZODIAZOCINES l-( p-ethoxyphenyl 1 2.3.4. 5.6-hexahydro-2.S-benzodiazocine 1,2.3,4,5.6-hexahydrol ,9- dimethyl-Z,S-benzodiazocine B-ethyll ,2,3 ,4,5 ,-hexahydro -l-phenyl-2,5-benzodiazocine l,2,3,4,5,6-hexahydro8,9- dimethyl-l-phenethyl-2,5- benzodiazocine DIHYDROlMlDAZOlSOlNDOLOLS 5-(4-ethoxyphenyl)-2,3- dihydro-5H-imidazo[2, l -a] isoinclol- S-ol 2,3-dihydro-5,S-dimethyl- 5H-imidazo[ 2,l-a]isoindol -5-ol 2,3-dihydro-7,8-dimethyl-5- (Z-phene thyl )-5 H-imidazo [2,l-a1isoindol-5-ol 8-fluorol ,2,3,4,5,6-hexahydrol -(p-tolyl )-2,5- benzodiazocine What is claimed is:

l. A process for the production of a compound having the formula:

wherein R R and R are defined as above, with a mineral acid, to form the mineral acid addition salt of a phthalimidine of the formula:

n-ca cn tm wherein R,, R and R are defined as above, reacting said phthalimidine acid addition salt with a sulfonyl halide selected from the group consisting of those having the formula:

wherein R is selected from the group consisting of lower alkyl, phenyl, monohalophen yl, dihalophenyl, m0no(lower) alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl, mono(lower)alkoxyphenyl and di(lower)alkoxyphenyl and X is halogen, in pyridine at a temperature that is in the range from about C. to about 115C. for a period from about 2 hours to about 10 hours, to form a compound of the formula:

. 0 ll 2 \L wherein R R R and R are defined as above, and by drolyzing said sulfonylimidazoisoindolone by treatment with from about 80 to about lOO percent sulfuric acid, to form a sulfate of the formula:

wherein R R and R are defined as above, and then contacting said sulfate with a base.

2. A process as described in claim 1 wherein the mineral acid is hydrochloric acid; the sulfonylation reaction is conducted with a sulfonyl chloride in pyridine at the reflux temperature of the reaction mixture for about two hours; the hydrolysis and rearrangement is conducted with percent sulfuric acid; and the base 

1. A PROCESS FOR THE PRODUCTION OF A COMPOUND HAVING THE FORMULA:
 2. A process as described in claim 1 wherein the mineral acid is hydrochloric acid; the sulfonylation reaction is conducted with a sulfonyl chloride in pyridine at the reflux temperature of the reaction mixture for about two hours; the hydrolysis and rearrangement is conducted with 90 percent sulfuric acid; and the base is sodium bicarbonate. 